Adhesive emulsion for medical purposes made from ethylene-vinyl acetate copolymers and adhesive resins

ABSTRACT

A pressure sensitive adhesive for medicinal application purposes, based on ethylene-vinyl acetate copolymers is characterized in that it contains as polymer component (A) an ethylene-vinyl acetate copolymer or a combination of at least two ethylene-vinyl acetate copolymers, and as component (B) an adhesive resin or a combination of adhesive resins at a portion of up to 55%-wt, relative to the sum of components (A) and (B) without active substances or other auxiliary substances.

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/EP02/03584 which has an Internationalfiling date of Mar. 30, 2002, which designated the United States ofAmerica.

The present invention relates to pressure sensitive adhesives which areproduced on the basis of ethylene-vinyl acetate copolymers and adhesiveresins and which are suitable for medical application purposes,especially as a component of pressure-sensitive adhesive skin-contactlayers. The invention further relates to pressure sensitive adhesivelayers and active substance-containing pressure-sensitive adhesivematrix layers, as well as to transdermal therapeutic systems containingsuch pressure sensitive adhesives. The invention, in addition, comprisesprocesses for the manufacture of such pressure sensitive adhesives, andof pressure sensitive adhesive layers and transdermal systems which usethe pressure sensitive adhesives.

Pressure sensitive adhesives (PSA) are frequently utilized in themedical field for making self-adhesive skin-contact layers, for examplein wound plasters or transdermal therapeutic systems (TTS). Suchpressure sensitive adhesives can generally be regarded as high-viscousliquids which after shortly and slightly pressing them on the skinimmediately and permanently adhere thereto. Due to theirviscoelasticity, such pressure sensitive adhesive layers are very wellcapable of conforming to the skin surface of the various zones of thebody. The pressure sensitive adhesives which are currently used mostfrequently are as a rule based on synthetic rubber polymers,polyacrylates or silicones.

In transdermal therapeutic systems, layers of pressure sensitiveadhesive frequently simultaneously serve as an active substancereservoir. In this case, the pressure sensitive adhesive, apart from itsfunction as adhesive, also has the function of an active substancereservoir and at the same time of controlling the release of activesubstance (“matrix-controlled TTS”).

With regard to the reservoir function it must be borne in mind that thepressure sensitive adhesive used has to be compatible with therespective active substances which are being employed. In particular,the pressure sensitive adhesive must not lead to a degradation ordecomposition of the active substance, and the chemical interactionsbetween the pressure sensitive adhesive and the active substance shouldbe as little as possible. In addition, it is demanded that the adhesivepower of the active substance reservoir not be adversely affected evenif larger amounts of active substance are incorporated.

Looking at the known compositions of the types of pressure sensitiveadhesive of commercially available “matrix-controlled” TTS, pressuresensitive adhesives based on polyacrylates appear to best fulfil theabove mentioned requirements. Apart from their very good autoadhesion,polyacrylates, by contrast to silicones and synthetic rubber polymers,have a high load capacity. Also of advantage is the relatively low skinirritating potential of polyacrylate-based pressure sensitive adhesivelayers.

However, in polyacrylate pressure sensitive adhesives, the polarity orpresence of functional groups in the polymer backbone can havedisadvantageous effects; especially in the case of basic, but also ofhydrolysis-unstable active substance compounds, there may occurstability and/or release problems as a result of chemical interactions.A further problem when using polyacrylates as pressure sensitiveadhesive active substance matrix is the often necessary addition ofchemical cross-linking agents in order to prevent “cold flow” (lateralflowing apart of the active substance matrix and emergence of thepressure sensitive adhesive mass at the lateral margins of the punchedTTS during storage, due to insufficient cohesion in the pressuresensitive adhesive). However, the cross-linking agents added arefrequently the cause of stability problems on account of chemicalinteractions with the active substances contained in the activesubstance reservoir of the TTS; if titanium-containing cross-linkingagents are used, skin-irritations may occur, in addition.

In other types of TTS, copolymers of ethylene and vinyl acetate (EVAcopolymers, e.g. the commercial product EVATANE®) are used as basematerial for the active substance reservoir, e.g. in the TTS “NicodermCQ” or in the TTS “Testoderm 15” for the active substances nicotine andtestosterone, respectively. However, since EVA copolymers have noautoadhesion, i.e. they are not pressure sensitive adhesive, in certainTTS adhesion to the skin must be ensured by means of an additionalpressure sensitive adhesive layer. In such TTS, EVA copolymers aremoreover also used in the form of membranes serving as control membranefor controlling the active substance release (“membrane-controlledTTS”). In this type of TTS, the control of the drug delivery isaccomplished by a drug-specific pore size (microporous control membrane)or by the membrane thickness or membrane composition, e.g. EVA controlmembrane. However, EVA control membranes, too, like EVA-based activesubstance reservoirs, possess no pressure sensitive adhesive properties.

The task underlying the invention was therefore to providepressure-sensitive adhesive compositions that have good pressuresensitive adhesive properties, are as chemically inert as possible,especially with respect to medicinal active substances, and which havethe above mentioned advantageous properties of the known polyacrylatepressure-sensitive adhesives. At the same time, it is demanded that toincrease internal cohesion no addition of cross-linking agents should benecessary. Furthermore, the portion of polar or functional groups in thepolymer backbone should at the same time be minimized. The pressuresensitive adhesive compositions are moreover to enable a control of therelease of active substance.

Surprisingly, this task is solved by pressure sensitive adhesives basedon ethylene-vinyl acetate (EVA) copolymers which according to claim 1contain an addition of adhesive resin(s).

Consequently, a pressure sensitive adhesive according to the presentinvention contains a polymer component (A), which is an ethylene-vinylacetate copolymer or a combination of at least two ethylene-vinylacetate copolymers, and a component (B), which is an adhesive resin or acombination of adhesive resins, the portion of component B amounting to55%-wt, relative to the sum of components (A) and (B) without activesubstances or other auxiliary substances (i.e. relative to the purepressure sensitive adhesive).

The present invention is based on the surprising observation that novelpressure sensitive adhesives are obtained if EVA copolymers aredissolved using suitable organic solvents under addition of heat, and ifthen adhesive resins e added in a specific mixing ratio; it is notnecessary here to add cross-linking agents or plasticizers.

In this connection, it is of advantage that the adhesive resin portionis relatively small, compared to pressure sensitive adhesives based onsynthetic rubber polymers (e.g. styrene-isoprene-styrene (SIS) blockcopolymers or styrene-butadiene-styrene (SBS) block copolymers, whichnecessitate markedly over 60%-wt of adhesive resin additives to obtainsufficiently pressure-sensitive adhesive properties. Such a high contentof adhesive resin can, however, lead to skin irritations.

By contrast, in the pressure sensitive adhesives according to theinvention, an adhesive resin content of at the most 55%-wt (relative tothe sum of components A and B, without active substances or otherauxiliary substances) is needed in order to achieve thepressure-sensitive adhesive properties demanded. In this manner it ispossible to maintain a low skin irritation potential.

Especially preferred is an adhesive resin portion in the range of from45 to 55%-wt; adhesives with this composition have particularly goodpressure sensitive adhesive properties. The adhesive resin portion(component B) should, however, be at least 25%-wt, still better at least30%-wt.

Adhesive resin additives are known to those skilled in the art ashydrogenated colophonic acid derivatives. Hydrogenated colophonic acidsor their derivatives have for quite some time been used as basematerials in pressure sensitive adhesive patches. Colophonic acids arecontained in the natural product colophony, which is obtained bydistillation of softwood balsam or by extraction from softwood stubs ofpredominantly subtropic-Mediterranean climatic zones.

For producing the pressure sensitive adhesives according to theinvention, such colophonic acids are preferably used as have beenpartially or completely hydrogenated, in order to protect them againstthe influence of oxygen and to increase their chemical inertia, and havebeen esterified at their carboxyl group to improve alkali stability andlikewise to increase chemical inertia. Especially preferred in thisconnection are methyl esters, glycerol esters, pentaerythritol esters,maleic acid-modified pentaerythritol esters, maleic acid-modifiedglycerol esters, or triethylene glycol esters of hydrogenated colophonicacids. Apart from these, other skin-tolerated derivatives ofhydrogenated colophony may be used, as well as corresponding esters ofnon-hydrogenated colophonic acids or of non-hydrogenated colophony.

As component A are preferably taken into consideration suchethylene-vinyl acetate copolymers as have a high vinyl acetate contentof at least 28%-wt, relative to the monomer composition. Incorporationof the vinyl acetate monomer, which is more strongly polar compared toethylene, leads to a reduction of the glass transition temperature and,in conjunction therewith, to a reduction of the crystalline portions inthe EVA copolymers. As a consequence, viscosity is lowered, swellabilityincreases, and the above-mentioned EVA copolymers—either with theabove-described adhesive resins in suitable solvent mixtures, or fromthe melt—can form adhesive and readily processable (that is, liquid orspreadable) pressure sensitive adhesive masses.

Best results are obtained where the portion of the EVA copolymer(s) isin the range of from 46 to 55%-wt, relative to the sum of the components(A) and (B). Preferably, the portion of component (A) is at least25%-wt, especially at least 15%-wt.

The pressure sensitive adhesive masses of the invention are, asdescribed, produced on the basis of EVA copolymers and adhesive resins,which constitute the base components of these pressure sensitiveadhesives. To make pressure sensitive adhesive layers or activesubstance-containing layers, it is possible to add active substances aswell as additives such as e.g. skin penetration-enhancing substances.Preferably, the pressure-sensitive adhesive portion in an activesubstance-containing layer or active substance matrix amounts to atleast 60%-wt, with particular preference at least 75%-wt.

By contrast, with the pressure sensitive adhesives according to thepresent invention, an addition of plasticizers or cross-linking agentsfor adjusting the adhesion or cohesion balance is not necessary; thus,according to one preferred embodiment such additives are not utilized.Preferably, there are also no other pressure sensitive adhesivepolymers, such as polyacrylates, added to the pressure sensitiveadhesives of the invention.

The pressure sensitive adhesives according to the present invention canbe used in numerous ways for the production of active substance-free oractive substance-containing layers with pressure-sensitive adhesion tothe skin. They are, in particular, suitable for producing activesubstance-containing pressure sensitive adhesive layers or adhesivematrices for active substance release in the field of human orveterinary medicine, e.g. as components of transdermal therapeuticsystems. Apart from this, these pressure sensitive adhesives can also beused in the manufacture of adhesive dressings, fixation patches orself-adhesive electrodes, or for the production of pressure sensitiveadhesive layers of TTS which are per se not adhesive.

Because of their advantageous properties and their sufficient adhesion(FIG. 4) the pressure sensitive adhesives according to the invention areespecially suited for the production of the active substance matrix oftransdermal therapeutic systems.

Preferably, such a system is configured as a single-layer matrix systemwhich consists of a substantially active substance-impermeable backinglayer, and the actual active active-substance-containing matrix layer,as well as a detachable protective layer. A TTS matrix system designedin this way stands out for its relatively simple and economicalmanufacture. It is further preferred that the active substance matrix bea single-phase system.

Preferably the TTS according to the invention contain an activesubstance portion in the range of 0.1 to 50%-wt., relative to thepressure sensitive adhesive layer or the active substance matrix.According to a further preferred embodiment, the adhesive resin portionin the TTS amounts to less than 50%-wt, with particular preference 39 to49%-wt, relative to the pressure sensitive adhesive layer or activesubstance matrix.

By the inventive combination of EVA copolymers with adhesive resin(s) toform a homogenous, single-phase pressure sensitive adhesive matrix, itis possible to combine the advantages of matrix-controlled andmembrane-controlled reservoir systems in one system. This represents anessential advantage over the state of the art since the control membrane(due to lacking adhesive power) in membrane-controlled systems mustusually be equipped with an additional, pressure sensitive adhesivelayer or with a pressure sensitive adhesive margin (superimposed patch),which makes their manufacture more complicated.

In this connection it is of particular advantage that by selectingdifferent portions of vinyl acetate or ethylene in the EVA copolymer(component A) it is possible to control the diffusion, respectively therelease, of active substance (cf. FIGS. 1A,B and FIGS. 2A,B).

Because of this property of the pressure sensitive adhesives accordingto the invention, it is also possible to use these adhesives to producecontrol membranes which, by contrast to known control membranes, arepressure sensitive adhesive. Such pressure sensitive adhesive EVAcontrol membranes or control layers can be used as control membrane inmembrane-controlled reservoir systems or as additional skin spread(skin-contact layer) in matrix-controlled TTS if the matrix itself doesnot have adhesive properties.

The pressure sensitive adhesives according to the present invention cantherefore be utilized for producing active substance-containing oractive substance-free layers of TTS, as well as of control membranes orcontrol layers. The invention thus relates to TTS having a structurethat is known per se, comprising an active substance-containing matrixor an active substance reservoir, a backing layer and a detachablebacking layer, these TTS containing at least one activesubstance-containing or active substance-free layer which is made from apressure sensitive adhesive according to the invention or which containssuch pressure sensitive adhesive.

The structure of the TTS according to the invention comprises—apart froman active substance matrix—an active substance-impermeable backinglayer, and a likewise active substance-impermeable, peelable protectivefilm.

Suitable as backing layer are first of all polyesters which arecharacterized by particular strength, but also other skin-toleratedplastics such as, for example, polyvinyl chloride, ethylene vinylacetate, vinyl acetate, polyethylene, polypropylene, cellulose derivatesand many others. In the individual case, the backing layer may beprovided with an additional layer, e.g. by vapour deposition with metalsor other diffusion-blocking additives such as silicon dioxide, aluminiumoxide or similar substances known to those skilled in the art.

For the detachable protective layer, the same materials may be used asare used for the backing layer, provided that the film is madedetachable by a suitable surface treatment such as, for example,siliconization. Other detachable protective layers may, however, also beused, such as polytetrafluorethylene-treated paper, cellophane,polyvinyl chloride, or similar materials.

Apart from the active substance(s), the pressure sensitive adhesivematrix according to the present invention may optionally containpenetration-enhancing substances in principle known to those skilled inthe art. Penetration enhancers compatible with the pressure sensitiveadhesive matrix of the invention, and therefore preferred, are, forexample, saturated or unsaturated fatty acids, straight-chain orbranched fatty alcohols as well as their esters, polyhydric aliphaticalcohols, polyethylene glycols, sorbitane fatty acid esters as well astheir derivatives or fatty alcohol ethoxylates obtainable byethoxylation, or monocyclic monoterpenes. Penetration-enhancingsubstances are preferably added in a concentration of 0.1 to 30%-wt,relative to the pressure sensitive adhesives layer of the activesubstance matrix.

It has been found that the pressure sensitive adhesive layers on thebasis of EVA copolymers and adhesive resins according to the inventionare particularly suitable for transdermal delivery of hormones,especially of steroid hormones such as sex steroids, especially fornatural and/or synthetic estrogens and gestagens, both singly as well asin combination, e.g. estrogen/gestagen combinations. In this connectionit is of particular advantage that the systems according to the presentinvention show no tendency whatsoever towards recrystallization of theactive substance contained therein. The active substance matrix maycontain one or more estrogens, or estrogen(s) in combination with atleast one gestagen. The total concentration of these hormones in thiscase amounts to 0.1 to 15%-wt, relative to the active substance matrix.In the case of an estrogen-gestagen combination, it has provedparticularly advantageous if estrogen(s) and gestagen(s) are present ina molar ratio of 1:1 to 1:10.

Due to the mentioned properties of the pressure sensitive adhesivesaccording to the present invention, these adhesives are not onlysuitable as a matrix for neutral medicinal active substances (FIGS. 1A,Band FIGS. 2A,B) but especially for the manufacture of activesubstance-containing layers containing active substance(s) which is/aresubject to hydrolysis. Among these are, in particular, active substancemolecules with acetyl function, preferably acetyl-salicylic acid ordiamorphine, and acid or basic, or organic, ionic (FIG. 3) medicinalactive substances or their pharmaceutically acceptable salts.

Because of the chemical inertia (due to the lack of polar or functionalgroups) of the pressure sensitive adhesives according to the inventiontowards medicinal active substances, chemical interactions with theactive substances, such as irreversible acid-base reactions, are largelyexcluded. As a consequence, the release of active substance, and therebybioavailability, can not be adversely affected by these unwantedreactions, which is not the case with pressure sensitive adhesivematrices based on acrylate adhesives.

Furthermore, the pressure sensitive adhesives according to the inventionhave a good reservoir capacity since most of the active substances, bothlipophile and hydrophile, readily dissolve in EVA copolymers. It is, forexample, possible to achieve active substance loads of 10%-wt. (relativeto the active substance matrix) without the aid of solubilizers, e.g.with the highly hydrophile organic morphinium salt morphinium-N-acetylglycinate (Example 3), or with the highly lipophile gestagennorethisterone acetate. Such high load capacities cannot be achievedwith the pressure-sensitive adhesives based on polyisobutylene, or withsilicone adhesives (load capacity maximally 5%-wt.); the latter are, inaddition, very expensive.

The pressure sensitive adhesives and pressure sensitive adhesive layersaccording to the invention can be prepared both from the solution, usingorganic solvents or solvent mixtures, and from the melt. In solidifiedstate, the inventive pressure sensitive adhesives prepared from the meltalso possess the typical properties of pressure sensitive adhesives,i.e. strong adhesion, and good quick stick. These inventive pressuresensitive adhesives prepared from the melt are to be distinguished fromhot melt adhesives, which are used for industrial purposes. With thesehot melt adhesives, adhesion occurs during the cooling process, afterthe molten adhesive has been applied to the substrate. Because of thehigh melting temperature required for this process and the lack of quickstick, this type of hot melt adhesives, which are not pressure sensitiveadhesives, is not suitable for the production of TTS or medicinalplasters.

To prepare the pressure sensitive adhesives according to the inventionfrom the melt, first, esters of colophony are homogenized under elevatedtemperature (45-150° C., preferably 50-120° C., especially preferred ca.100° C.) by kneading and melting. Subsequently, ethylene-vinyl acetatecopolymer(s), and optionally active substance(s) and/or penetrationenhancers, are added and worked into the molten adhesive mass, this isfollowed by homogenization. The active substance-containing or activesubstance-free adhesive mass thus obtained can now be applied to adetachable protective layer by means of a hot melt coating line (nozzleapplication system and/or extruder). The production can also beaccomplished by extrusion.

To prepare the pressure sensitive adhesives according to the inventionfrom a solution, ethylene-vinyl acetate copolymer(s) (component A)is/are dissolved at elevated temperature (preferably 40-75° C.,especially 45-55° C.) in an organic solvent mixture, while stirring.Preferably, a gasoline- and/or propyl acetate-containing solvent mixtureis used for this purpose, the following mixtures being particularlypreferred: gasoline/propyl acetate (2:1), gasoline/butanone (1:1),gasoline/propyl acetate/butanone (1:1:1), hexane/propyl acetate/acetone(1:1:1) (all values refer to volume content). Subsequently adhesiveresin(s) (component B) are incorporated by stirring and underhomogenisation until complete dissolution occurs, likewise at elevatedtemperature as indicated. Addition of optional components (e.g. activesubstances, enhancers) and coating is performed as described above. Toremove the solvents, the layer thus obtained is subjected to drying atelevated temperature (preferably at ca. 30-80° C., especially at 50° C.

In the following, the invention will be explained in more detail by wayof examples and illustrations.

Using the prepared active substance-containing pressure sensitiveadhesive matrix systems according to the invention, permeationmeasurements were performed on the in-vitro skin model by using humanskin epidermis (FIG. 1-3), or with the aid of modified Franz diffusioncells. In all cases, the acceptor medium was isotonic saline with 0.1%addition of NaN3 as preserving agent, thermostatted to 37° C.

EXAMPLE 1

Preparing a Self-Adhesive, Active Substance-Containing Film(17-β-estradiol and Norethisterone Acetate)

In 80 g of a solvent mixture, consisting of 2 parts special boilingpoint gasoline type 80/110 and 1 part propyl acetate, is introduced 54 gof an EVA copolymer, with 40%-wt of vinyl acetate and a melt flow indexof 55 (EVATANE 40/55®), and dissolved by stirring und under addition ofheat at 50° C. After approx. 30 minutes of stirring, a viscous,colourless up to slightly opaque solution is obtained. In this solutionwas then introduced 66 g of the adhesive resin Foral® 85 E, and this wasstirred, likewise at 50° C., until complete dissolution occurred (ca. 15min). A 50%, low-viscous, yellowish and slightly opaque solution(adhesive solution I) resulted which after having cooled down was stillpresent as a stirrable adhesive solution. To prepare the self-adhesive,active substance-containing film 9.88 g of adhesive solution I was used,into which 2.4 g of 17-β-estradiol, and subsequently 9.6 g ofnorethisterone acetate, were introduced in portions by stirring. Ifnecessary, 1000 μl of methanol can be added to reduce the viscosity ofthe mass composition. This mass composition is homogenized for a totalof 30 min at a stirring speed of 350 rpm. This is followed by degassingfor 15 minutes at 45° C. in the ultrasonic bath to remove excessive airfrom the mass.

The active substance-containing adhesive solution is then, by means of asheeting-out doctor knife, spread with a wet-layer thickness of 300 μmto a siliconised polyethylene terephthalate film. Thereafter thesolvents are removed by drying for half an hour at 50° C. in a dryingcupboard with waste air guidance. The solvent-free, activesubstance-containing adhesive film is subsequently covered with a15-μm-thick polyester film (as backing layer) by laminating. The portionof adhesive contained in the matrix after completion of the preparationamounts to 88%-wt; of this, 48.4%-wt is made up by the adhesive resin.

EXAMPLE 2

Preparation of a Self-adhesive, Active Substance-Containing Film(17-β-estradiol and Norethisterone Acetate)

In 60 g of a solvent mixture, consisting of 2 parts specialboiling-point gasoline type 80/110 and 1 part propyl acetate, isintroduced 69 g of an EVA copolymer with 33%-wt of vinyl acetate and amelt index of 400 (EVATANE 33/400®) and dissolved by stirring and underaddition of heat at 50° C. After stirring for ca. 30 min, a viscous,colourless up to slightly opaque solution was obtained. In this solutionwas then introduced 56 g of the adhesive resin Foral® 85 E and this wasstirred, likewise at 50° C., until complete dissolution occurred (ca. 15min). There resulted a 58%, low-viscous, yellowish and slightly opaquesolution (adhesive solution II) which even after having cooled down wasstill present as a stirrable adheesive solution.

To prepare the self-adhesive, active substance-containing film, 7.59 gof adhesive solution II was used, into which 2.4 g of 17-β-estradioland, subsequently, 9.6 g of norethisterone acetate were introduced inportions by stirring. The further preparation of the adhesive film wasperformed as described in Example 1.

The portion of adhesive in the matrix after completion of thepreparation amounted to 88%-wt; of this, 39.6%-wt was made up by theportion of adhesive resin.

EXAMPLE 3

Preparation of a Self-Adhesive, Active Substance-Containing Film(morphinium-N-acetylglycinate as Active Substance)

The preparation is performed as described under Example 1, but with anadhesive resin portion of 49.5%-wt in the matrix, and withmorphinium-N-acetylglycinate (10%-wt.) as active substance. EVATANE40/55® was again used as EVA copolymer.

TABLE 1 Active substance-containing films according to Examples 1 to 3Example 1 Example 2 Example 3 EVA copolymer type 40/55 33/400 40/55Vinyl acetate content in 40 33 40 the copolymer (Gew.-%) EVA content inthe matrix 39.6 48.4 40.5 (in %-wt.) Adhesive resin portion in 48.4 39.649.5 the matrix (%-wt) Vinyl acetate content in 15.84 15.972 16.20 thematrix (%-wt) Ethylene portion in the 23.76 32.428 24.3 matrix (%-wt)Active substances Oes: 2.4 Oes: 2.4 Morphinium-N- (%-wt) NeA: 9.6 NeA:9.6 acetylglycinate: 10Explanation of the Figures

FIG. 1 to 3 show the results of the permeation measurements performedwith Examples 1 to 3.

FIG. 1A shows results of permeation measurements with arecrystallisation-free matrix of the invention according to Example 1with a portion of 48.4%-wt of adhesive resin, and 17-β-estradiol(2.4%-wt.; as semihydrate) and norethisterone acetate (9.6%-wt) asactive substance, without addition of enhancers, cross-linking agents,plasticizers, crystallisation inhibitors or other auxiliaries.

As a comparison example was used a commercial reference combination TTS(Evorel Conti®; Cilag, CH) containing 2.5%-wt of 17-β-estradiol (assemihydrate), 8.75%-wt of norethisterone acetate, 2%-wt of Myprogat 90and 86.75%-wt of Duro-Tak 2287. Myprogat 90 is a water-absorbing agent,not an enhancer.

FIG. 1A shows a comparison of the accumulated permeation values ofnorethisterone acetate (abbreviated: “NeA”)

FIG. 1B:

Shows results of permeation measurements with a matrix of the inventionaccording to Example 1, as in FIG. 1A, but here representing acomparison of the accumulated permeation values of 17-β-estradiol(abbreviated: “Oes”).

FIG. 2A:

Shows results of permeation measurements with a matrix of the inventionaccording to Example 2 with a portion of 39.6%-wt of adhesive resin, aportion of 15.972%-wt of vinyl acetate (relative to the entire matrix),as well as 17-β-estradiol (2.4%-wt; as semihydrate) and norethisteroneacetate (9.6%-wt) as active substances, without addition of enhancers,cross-linking agents, plasticizers, crystallisation inhibitors or otherauxiliary substances. As comparison example was used a matrix of theinvention according to Example 1 with almost the same portion of vinylacetate (15.84%-wt), but lower ethylene content (23.76%-wt) and higheradhesive resin portion (48.4%-wt.).

FIG. 2A shows a comparison of accumulated permeation values ofnorethisterone acetate (“NeA”).

FIG. 2B:

shows results of permeation measurements with a matrix of the inventionaccording to Example 2, as in FIG. 2A, but here representing acomparison of accumulated permeation values of 17-β-estradiol (“Oes”).

FIG. 3:

shows results of permeation measurements with a matrix of the inventionaccording to Example 3 with a portion of 49.5%-wt of adhesive resin, andwith morphinium-N-acetylglycinate as active substance, without additionof enhancers, cross-linking agents, plasticizers or other auxiliarysubstances.

As comparison example (reference) was used a pressure sensitive adhesivematrix based on polyacrylates with cross-linking agent and with 25%-wtof oleic acid as enhancer. The active substance load was the same inboth cases (10%-wt).

FIG. 4:

shows a comparison of values of adhesive power measured on TTS of theinvention based on EVA copolymers and adhesive resins according toExamples 1 and 2, compared with adhesive power values of a reference TTS(Evorel Conti®) based on acrylate.

The measurements are based on the test method according to “PeelAdhesion 90° Test” (test plate: aluminium; peel-off speed 300 mm/min;tensile-testing machine according to DIN51221, part 1).

1. A pressure sensitive adhesive composition based on ethylene-vinylacetate copolymers, wherein the pressure sensitive adhesive compositionconsists of: (i) a polymer component (A), which is an ethylene-vinylacetate copolymer or a combination of at least two ethylene-vinylacetate copolymers, and (ii) a component (B), which is an adhesive resinor a combination of adhesive resins at a portion of up to 55%-wt,relative to the sum of the components (A) and (B), wherein components(A) and (B) are present in dissolved form in a mixture of organicsolvents selected from the group consisting of gasoline/propyl acetatein proportion 2:1 by volume, gasoline/butanone in proportion 1:1 byvolume, gasoline/propyl acetate/butanone in proportion 1:1:1 by volumeand hexane/propyl acetate/acetone in proportion 1:1:1 by volume.
 2. Thepressure sensitive adhesive composition according to claim 1, wherein atleast one of the ethylene-vinyl acetate copolymer(s) has a vinyl acetatecontent of at least 28%-wt, relative to the monomer composition.
 3. Thepressure sensitive adhesive composition according to claim 1, whereinsaid polymer component A is at least 46%-wt, relative to the sum ofcomponents A and B.
 4. The pressure sensitive adhesive compositionaccording to claim 1, wherein the portion of said component B is atleast 45%-wt and up to 55%-wt, relative to the sum of components A andB.
 5. The pressure sensitive adhesive composition according to claim 1,wherein the adhesive resin(s) are ester(s) of colophony and/or ester(s)of hydrogenated colophony.
 6. The pressure sensitive adhesivecomposition according to claim 5, wherein the esters of colophony and/oresters of hydrogenated colophony are selected from the group consistingof methyl esters, glycerol esters, pentaerythritol esters,maleic-acid-modified pentaerythritol esters, maleic-acid-modifiedglycerol esters and triethylene glycol esters.
 7. The pressure sensitiveadhesive composition according to claim 1, wherein said pressuresensitive adhesive composition is free of any plasticizers andcross-linking agents.
 8. A process for producing a pressure sensitiveadhesive composition, comprising: i) dissolving at least oneethylene-vinyl acetate copolymer, as polymer component (A) in a mixtureof organic solvents, at a temperature of from 40 to 75° C., wherein themixture of organic solvents is selected from the group consisting ofgasoline/propyl acetate in proportion 2:1 by volume, gasoline/butanonein proportion 1:1 by volume, gasoline/propyl acetate/butanone inproportion 1:1:1 by volume, and hexane/propyl acetate/acetone inproportion 1:1:1 by volume; and ii) incorporating an adhesive resin or acombination of adhesive resins as component B at a portion of up to55%-wt relative to the sum of the components (A) and (B) into themixture of step i) by stirring and homogenizing at a temperature of from40 to 75° C. until complete dissolution occurs.
 9. The process accordingto claim 8, wherein the adhesive resin is selected from the groupconsisting of esters of colophony and esters of hydrogenated colophony.